Medium-molecular-weight compound conjugate for improving pharmacokinetic profile of medium-molecular-weight compound and method of producing the same

Abstract

Provided is a medium-molecular-weight compound conjugate capable of improving pharmacokinetic profile of a medium-molecular-weight compound, that is easy to obtain, safer to a biological body, and useful in vivo such as a nucleic acid aptamer, and a method of producing the same. The PMPC-medium-molecular-weight compound conjugate of the present invention is obtained by conjugating PMPC (poly-2-(methacryloyloxy)ethyl phosphoryicholine) to a medium-molecular-weight compound.

1 . A PMPC-medium-molecular-weight compound conjugate for improving pharmacokinetic profile of a medium-molecular-weight compound, wherein PMPC (poly-2-(methacryloyloxy)ethyl phosphorylcholine) is conjugated to the medium-molecular-weight compound. 
     
     
         2 . The PMPC-medium-molecular-weight compound conjugate according to  claim 1 , wherein the medium-molecular-weight compound is a single-stranded or double-stranded oligonucleotide having a molecular weight of 50 kDa or less. 
     
     
         3 . The PMPC-medium-molecular-weight compound conjugate according to  claim 2 , wherein the oligonucleotide is a DNA aptamer or an RNA aptamer. 
     
     
         4 . The PMPC-medium-molecular-weight compound conjugate according to  claim 1 , wherein the medium-molecular-weight compound is a peptide or a protein having a molecular weight of 50 kDa or less. 
     
     
         5 . The PMPC-medium-molecular-weight compound conjugate according to  claim 1 , wherein the medium-molecular-weight compound is a nanobody, a Fab fragment of an antibody, a peptide hormone, a chemokine, a cytokine, a linear or cyclic peptide having a function to bind to a specific protein. 
     
     
         6 . The PMPC-medium-molecular-weight compound conjugate according to  claim 1 , wherein PMPC to be conjugated has a degree of polymerization n of n=50 to 800. 
     
     
         7 . A method of producing a PMPC-medium-molecular-weight compound conjugate comprising:
 a polymerization step of subjecting MPC to polymerization reaction using an initiator to obtain PMPC having a terminal primary amino group, and   a binding step of chemically binding a medium-molecular-weight compound and PMPC using the terminal primary amine of PMPC.   
     
     
         8 . The method according to  claim 7 , further comprising, when PMPC with a protected terminal primary amino group is obtained in the polymerization step, a deprotecting step of removing a protecting group of the terminal primary amino group of PMPC after the polymerization step. 
     
     
         9 . The method according to  claim 7 , wherein when the initiator in the polymerization step is 2-(tert-butyloxycarbonyl-aminoethyl) isobutylbromide, deprotection reaction that removes Boc protecting group of the terminal primary amino group of PMPC is performed following the polymerization reaction. 
     
     
         10 . The method according to  claim 7 , wherein the medium-molecular-weight compound is a single-stranded or double-stranded oligonucleotide having a molecular weight of 50 kDa or less. 
     
     
         11 . The method according to  claim 10 , wherein the oligonucleotide is a DNA aptamer or an RNA aptamer. 
     
     
         12 . The method according to  claim 7 , wherein the medium-molecular-weight compound is a peptide or a protein having a molecular weight of 50 kDa or less. 
     
     
         13 . The method according to  claim 7 , wherein the medium-molecular-weight compound is a nanobody, a Fab fragment of an antibody, a peptide hormone, a chemokine, a cytokine, a linear or cyclic peptide having a function to bind to a specific protein. 
     
     
         14 . The method according to  claim 7 , wherein the medium-molecular-weight compound and PMPC are chemically bound through a linker. 
     
     
         15 . The method according to  claim 14 , wherein the linker and PMPC are bound by condensation reaction of an active ester and an amine, or condensation reaction of an amine and an intermediate formed by activating an ester or a carboxylic acid in a reaction system or outside a reaction system. 
     
     
         16 . The method according to  claim 15 , wherein the active ester is N-hydroxysuccinimide ester. 
     
     
         17 . The method according to  claim 7 , wherein the medium-molecular-weight compound has a functional group used for click reaction, and the functional group and PMPC are bound by click reaction.